Human herpesvirus 8 (HHV8) is a recently described DNA virus with demonstrated oncogenic and angiogenic properties. HHV8 is causally associated with Kaposi's sarcoma, a tumor of endothelial cell origin and primary effusion lymphoma (PEL), a rare B cell lymphoma in immunosuppressed patients. Growth of HHV8-infected endothelial cells is correlated with increased expression of vascular endothelial growth factors (VEGFs) and VEGF receptors. HHV8-infected tumor cells also secrete factors capable of sustaining the proliferation of uninfected endothelial cells in trans. Delineation of the mechanisms by which HHV8 genes affect endothelial cell growth is critical to an understanding of HHV8-induced angiogenesis and malignant transformation. Elucidation of the pathways involved in proliferation of HHV8-infected endothelial cells is likely to yield insights into general mechanisms of tumor associated angiogenesis. Our long-term goal is to gain an understanding of endothelial cell gene regulation that will allow the development of molecular prevention and treatment strategies aimed at angiogenesis in a broad range of human cancers. We therefore proposed to test the following hypotheses: 1. HHV8 proteins activate endothelial cell genes important for proliferation. 2. HHV8 genes that are involved in transformation of primary cells directly or indirectly activate endothelial cell genes. To test these hypotheses, we proposed studies with the following Specific Aims: 1. To determine the role of two Kaposi sarcoma-associated herpesvirus trans-activating genes (Rta and ORF57) in the regulation of endothelial cell genes important in vascular proliferation. 2. To develop a method of producing recombinant HHV8 with targeted gene mutations to determine which HHV8 genes are required for endothelial cell transformation and proliferation.